Syphilis, a multi-stage sexually transmitted disease caused by the spirochete Treponema pallidum (Tp), continues to be a major worldwide public health problem. The World Health Organization (WHO) estimates that approximately 10.6 million new syphilis cases occur yearly throughout the globe. The clinical manifestations of syphilis reflect the propensity of Tp to disseminate systemically and induce a chronic inflammation which occurs in stages, being secondary syphilis (SS) the focus of this proposal. Despite the robust nature of the adaptive and humoral immune responses during SS, including the emergence of high titers of opsonic antibodies, it takes weeks to months for host defenses to gain control of the invading pathogen. How the bacterium is able to evade human host defenses, while at the same time evoking vigorous cellular and humoral immune responses, is the principal scientific objective of the current proposal. A careful analysis of Tps unique ultrastructural characteristics, which contains very few outer membrane proteins (OMPs), provides potential explanations for the paradoxical nature of SS. Inefficient antibody binding to the sparse spirochetal OMP antigenic targets is thought to allow a large proportion of spirochetes to shun antibody binding and opsonophagocytosis; a mechanism which we have shown is an essential requirement for Tp driven innate immune cell activation. The new finding that circulating natural killer (NK) cells reveal immunophenotypic alterations (emergence of a CD56negativeCD16high NK-cell subset), which exhibits both poor cytolytic activity and impaired cytokine production suggests that additional immunologic factors play a role in the duality of the immune response to Tp. We now propose a new syphilis immune-pathogenesis model, where antibodies to Tps rare OMPs are only capable of binding a sub-population of spirochetes, thus allowing immune escape of organisms and at the same time recognition and bacterial clearance of different tissues. Over time, the host's expanding repertoire of antibodies against these rare OMPs broadens and intensifies, leading to more efficient opsonophagocytosis, bacterial clearance and lesion resolution. To accomplish our goals and examine mechanistic aspects of the proposed model, we have formulated the following Specific Aims. In Aim 1: we will further characterize spirochete burdens, spirochete diversity and the antibody responses in the blood of secondary syphilis patients; and in aim 2: we will study the role of the dermal macrophage as a driver of both inflammation and spirochetal clearance in secondary syphilis patient's dermal lesions. And in aim 3, w will further characterize NK cells in blood of SS patients. In concert wit the Fogarty International Center's mission to reduce health disparities amongst nations, the planned activities will also: (1) support collaborative syphilis immunobiology research between the LMIC PI and the US collaborators (2) strengthen CIDEIMs research capabilities and technical base; (3) continue providing needed epidemiological data about venereal syphilis for that region of Colombia.